Molecular and clinical determinants of response and resistance to rucaparib for recurrent ovarian cancer treatment in ARIEL2 (Parts 1 and 2)

Càncer d'ovaris; Biomarcadors tumoralsCáncer de ovarios; Biomarcadores tumoralesOvarian cancer; Tumour biomarkersARIEL2 (NCT01891344) is a single-arm, open-label phase 2 study of the PARP inhibitor (PARPi) rucaparib in relapsed high-grade ovarian carcinoma. In this post hoc exploratory biomarker analysis of pre- and post-platinum ARIEL2 samples, RAD51C and RAD51D mutations and high-level BRCA1 promoter methylation predict response to rucaparib, similar to BRCA1/BRCA2 mutations. BRCA1 methylation loss may be a major cross-resistance mechanism to platinum and PARPi. Genomic scars associated with homologous recombination deficiency are irreversible, persisting even as platinum resistance develops, and therefore are predictive of rucaparib response only in platinum-sensitive disease. The RAS, AKT, and cell cycle pathways may be additional modulators of PARPi sensitivity

Anterolateral ligament reconstruction does not delay functional recovery, rehabilitation, and return to sport after anterior cruciate ligament reconstruction. A matched-pair analysis from the SANTI (Scientific ACL Network International) Study Group

Purpose: To determine whether the addition of an anterolateral ligament reconstruction (ALLR) resulted in delayed functional recovery (based on the Knee Santy Athletic Return to Sport [K-STARTS] score) at 6 months after anterior cruciate ligament reconstruction (ACLR). Methods: A retrospective analysis of prospectively collected data from consecutive pa- tients who underwent an ACLR between September 2017 and December 2020 was conducted. Patients who received an isolated hamstring autograft (isolated ACLR group) were propensity matched in a 1:1 ratio to patients who received a hamstring autograft ACLR combined with an ALLR (ACLR-ALLR group). Outcome measures included the Tegner Activity Scale and the K-STARTS testda validated composite return-to-sports test (including the Anterior Cruciate LigamenteReturn to Sport After Injury scale, Qualitative Assessment of Single-Leg Landing tool, limb symmetry index, and ability to change direction using the Modified Illinois Change of Direction Test). Results: The study included 111 matched pairs. At 6 months postoperatively, there were no significant differences between groups in the overall K-STARTS score (65.4 for isolated ACLR vs 61.2 for ACLR-ALLR, P 1⁄4 .087) or the Tegner Activity Scale score (3.7 for isolated ACLR vs 3.8 for ACLR-ALLR, P 1⁄4 .45). In addition, an evaluation of the subscales of the K-STARTS score revealed no disadvantage across the domains of neuromuscular control, limb symmetry index, agility, or psychological readiness to return to sport when an ALLR was performed. Conclusions: The addition of ALLR at the time of ACLR does not delay functional recovery. Spe- cifically, at 6 months postoperatively, there was no disadvantage in patients undergoing ALLR-ACLR, when compared with those undergoing isolated ACLR, with respect to neuromuscular control, limb symmetry indices (hop tests), agility, or psychological readiness to return to sport

Stellar and thermal neutron capture cross section of ⁹Be

The neutron capture cross section of ⁹Be for stellar energies was measured via the activation technique using the Karlsruhe Van de Graaff accelerator in combination with accelerator mass spectrometry at the Vienna Environmental Research Accelerator. To characterize the energy region of interest for astrophysical applications, activations were performed in a quasistellar neutron spectrum of kT = 25 keV and for a spectrum at En = 473 ± 53 keV. Despite the very small cross section, the method used provided the required sensitivity for obtaining fairly accurate results of 10.4 ± 0.6 and 8.4 ± 1.0 μb, respectively. With these data it was possible to constrain the cross section shape up to the first resonances at 622 and 812 keV, thus allowing for the determination of Maxwellian-averaged cross sections at thermal energies between kT = 5 and 100 keV. In addition, we report a new experimental cross section value at thermal energy of σth = 8.31 ± 0.52 mb.This work was partly funded by the Austrian Science Fund (FWF), Projects No. P20434 and No. I428, and by the Australian Research Council, Projects No. DP140100136 and No. DP180100496

Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: integrated analysis of data from Study 10 and ARIEL2

Objective: An integrated analysis was undertaken to characterize the antitumor activity and safety profile of the oral poly(ADP-ribose) polymerase inhibitor rucaparib in patients with relapsed high-grade ovarian carcinoma (HGOC). Methods: Eligible patients from Study 10 (NCT01482715) and ARIEL2 (NCT01891344) who received a starting dose of oral rucaparib 600 mg twice daily (BID) with or without food were included in these analyses. The integrated efficacy population included patients with HGOC and a deleterious germline or somatic BRCA1 or BRCA2 (BRCA1/2) mutation who received at least two prior chemotherapies and were sensitive, resistant, or refractory to platinum-based chemotherapy. The primary endpoint was investigator-assessed confirmed objective response rate (ORR). Secondary endpoints included duration of response (DOR) and progression-free survival (PFS). The integrated safety population included patients with HGOC who received at least one dose of rucaparib 600 mg BID, irrespective of BRCA1/2 mutation status and prior treatments. Results: In the efficacy population (n = 106), ORR was 53.8% (95% confidence interval [CI], 43.8–63.5); 8.5% and 45.3% of patients achieved complete and partial responses, respectively. Median DOR was 9.2 months (95% CI, 6.6–11.6). In the safety population (n = 377), the most frequent treatment-emergent adverse events (AEs) were nausea, asthenia/fatigue, vomiting, and anemia/hemoglobin decreased. The most common grade ≥ 3 treatment-emergent AE was anemia/hemoglobin decreased. Treatment-emergent AEs led to treatment interruption, dose reduction, and treatment discontinuation in 58.6%, 45.9%, and 9.8% of patients, respectively. No treatment-related deaths occurred. Conclusions: Rucaparib has antitumor activity in advanced BRCA1/2-mutated HGOC and a manageable safety profile

Evolution of the one-phonon 2(1,ms)(+) mixed-symmetry state in N=80 isotones as a local measure for the proton-neutron quadrupole interaction

An inverse kinematics Coulomb excitation experiment was performed to obtain absolute E2 and M1 transition strengths in 134Xe. The measured transition strengths indicate that the 23+ state of 134Xe is the dominant fragment of the one-phonon 21, ms+ mixed-symmetry state. Comparing the energy of the 21, ms+ mixed-symmetry state in 134Xe to that of the 21, ms+ levels in the N = 80 isotonic chain indicates that the separation in energy between the fully-symmetric 21+ state and the 21, ms+ level increases as a function of the number of proton pairs outside the Z = 50 shell closure. This behavior can be understood as resulting from the mixing of the basic components of a two-fluid quantum system. A phenomenological fit based on this concept was performed. It provides the first experimental estimate of the strength of the proton-neutron quadrupole interaction derived from nuclear collective states with symmetric and antisymmetric nature

Factors of interrupting chemotherapy in patients with Advanced Non-Small-Cell Lung Cancer

<p>Abstract</p> <p>Background</p> <p>Little is known about prognosis of metastatic patients after receiving a first-line treatment and failure. Our group already showed in pre-treated patients enrolled in phase I clinical trials that a performance status (PS) > 2 and an LDH > 600 UI/L were independent prognostic factors. In this prospective study, which included 45 patients, we identified clinical and biological variables as outcome predictors in metastatic Non-Small Cell lung cancer after first line chemotherapy were identified.</p> <p>Findings</p> <p>Forty-five patients that were previously treated for metastatic disease from 12/2000 to 11/2005 in the comprehensive cancer centre (Centre Léon Bérard). Clinical assessment and blood parameters were recorded and considered. Patient prognostic factors for overall survival (OS) with a 0.05-significance level in univariate analysis were entered in a multivariate Cox model for further analysis.</p> <p>Patients' median age was 58.5 years (range: 37 - 76). Sixty two percent of the patients were PS = 0 or 1. After inclusion, nine patients received second-line (22.5%), and two received third-line chemotherapy (5%). Univariate analysis showed that the factors associated with reduced OS were: PS > 2, weight loss >10%, more than one line of chemotherapy treatment and abnormal blood parameters (hemoglobin (Hb), platelet and neutrophils counts). Multiple regression analysis confirmed that PS > 2 and abnormal hemoglobin were independent predictors for low overall survival. According to the presence of none (33%), 1 (37%) and 2 (30%) prognostic factors, median OS were 12, 5 and 2 months respectively.</p> <p>Conclusion</p> <p>From this prospective study, both PS and anemia were found as independent determinants of survival, we found that both PS and anemia were independent determinants of survival. The combination of poor PS and anemia is an effective strategy to predict survival in the case of patients with metastatic NSCLC receiving further treatment after the first line.</p

Diagnosis and management of anaemia and iron deficiency in patients with haematological malignancies or solid tumours in France in 2009-2010: the AnemOnHe study

OBJECTIVE: To describe the management of anaemia in 2009-2010 in France in patients with haematological malignancies (HM) or solid tumours (ST). METHODS: Retrospective observational study in 57 centres, enrolling adult patients with HM or ST treated for an episode of anaemia (duration of the episode &gt;/= 3 months occurring in the last 12 months). RESULTS: 220 patients with ST (breast, 18%; lung, 18%) and 56 with HM (lymphoma, 60%) were included (median age, 68 years; female, 53%). Mean haemoglobin level at anaemia diagnosis was 9.3 +/- 1.4 g/dL (&lt;8 g/dL for 16%) and 9.8 +/- 1.1g/dL (&lt;8 g/dL for 6%) in HM and ST patients, respectively. At least one parameter of iron deficiency (ferritin, transferrin saturation) was assessed in 26% of HM and 19% of ST patients. Treatment of anaemia included erythropoiesis-stimulating agents (ESA) for 98% of HM and 89% of ST patients. Iron was prescribed to 14% (oral, 12%; intravenous, 2%) of HM patients and to 42% (oral, 17%; intravenous, 25%) of ST patients. The rates of blood transfusions were high: 70% in HM and 46% in ST patients; transfusions alone or administrated with ESA were more frequent in patients with Hb &lt;8 g/dL. CONCLUSION: Although recent guidelines recommend evaluating iron deficiency and correcting anaemia by using intravenous iron, our study in cancer patients evidenced that ESA and blood transfusions are still frequently used as the treatment of anaemia in cancer patients. Iron deficiency is insufficiently assessed (only one patient among five) and as a consequence iron deficiency is most likely insufficiently treated

A European project on incidence, treatment, and outcome of sarcoma

Abstract BACKGROUND: Sarcomas are rare tumors (1-2% of all cancers) of mesenchymal origin that may develop in soft tissues and viscera. Since the International Classification of Disease (ICD) attributes visceral sarcomas (VS) to the organ of origin, the incidence of sarcoma is grossly underestimated. The rarity of the disease and the variety of histological types (more than 70) or locations account for the difficulty in acquiring sufficient personal experience. In view of the above the European Commission funded the project called Connective Tissues Cancers Network (CONTICANET), to improve the prognosis of sarcoma patients by increasing the level of standardization of diagnostic and therapeutic procedures through a multicentre collaboration. METHODS/DESIGN: Two protocols of epidemiological researches are here presented. The first investigation aims to build the population-based incidence of sarcoma in a two-year period, using the new 2002 WHO classification and the "second opinion" given by an expert regional pathologist on the initial diagnosis by a local pathologist. A three to five year survival rate will also be determined. Pathology reports and clinical records will be the sources of information.The second study aims to compare the effects on survival or relapse-free period - allowing for histological subtypes, clinical stage, primary site, age and gender - when the disease was treated or not according to the clinical practice guidelines (CPGs). DISCUSSION: Within CONTICANET, each group was asked to design a particular study on a specific objective, the partners of the network being free to accept or not the proposed protocol. The first protocol was accepted by the other researchers, therefore the incidence of sarcoma will be assessed in three European regions, Rhone-Alpes and Aquitaine (France) and Veneto (Italy), where the geographic distribution of sarcoma will be compared after taking into account age and gender. The conformity of the clinical practice with the recommended guidelines will be investigated in a French (Rhone Alps) and Italian (Veneto) region since the CPGs were similar in both areas